JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction

Abstract

The Activation-Induced Cell Death (AICD) is a stimulation-dependent form of apoptosis used by the organism to shutdown T-cell response once the source of inflammation has been eliminated, while allowing the generation of immune memory. AICD is thought to progress through the activation of the extrinsic Fas/FasL pathway of cell death, leading to cytochrome-C release through caspase-8 and Bid activation. We recently described that, early upon AICD induction, mitochondria undergo structural alterations, which are required to promote cytochrome-C release and execute cell death. Here, we found that such alterations do not depend on the Fas/FasL pathway, which is instead only lately activated to amplify the cell death cascade. Instead, such alterations are primarily dependent on the MAPK proteins JNK1 and ERK1/2, which, in turn, regulate the activity of the pro-fission protein Drp1 and the pro-apoptotic factor Bim. The latter regulates cristae disassembly and cooperate with Drp1 to mediate the Mitochondrial Outer Membrane Permeabilization (MOMP), leading to cytochrome-C release. Interestingly, we found that Bim is also downregulated in T-cell Acute Lymphoblastic Leukemia (T-ALL) cells, this alteration favouring their escape from AICD-mediated control.

PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism

“…2B). In line with this, while T cells fragment mitochondria upon activation (15,16,23), T cells stimulated in the presence of PD-L1 retain a more fused network ( Fig. 2C).…”

“…Of note, these data are shared also in a corresponding human context of colon tumor, in which tumor-infiltrating lymphocytic elements almost never co-express PD-1 and active Drp1. Mechanistically, we provided evidence that PD-1 signaling downregulates Drp1 activating phosphorylation on Ser616 (and consequently mitochondria fragmentation) via the inhibition of ERK1/2 kinases, which directly phosphorylate Drp1 on this residue (15,16,25). Also, our data indicate that concomitant PD-1-dependent inhibition of mTOR pathway contributes to such a reduced Drp1 activity.…”

“…Of note, both these pathways have been reported to modulate Drp1-dependent mitochondria fragmentation. Indeed, ERK1/2 directly phosphorylate Drp1 on Ser616 (25), as we already showed in T cells, too (15,16,26). Similarly, the mTOR pathway promotes mitochondria fragmentation via Drp1 activation (27), even though it is supposed to not directly phosphorylate Drp1, and rather acting through the modulation of ERK activity, as suggested in murine embryonic fibroblasts (27).…”

“…In addition, although we here provided evidence that Drp1 downregulation may be exploited by PD-1 signaling to reduce tumor-infiltrating T cell motility and proliferation, other processes may be touched as well. First, we recently reported that Drp1 is required to allow cytochrome-c release and activation of caspases during the Activation-Induced Cell Death (AICD) progression in T cell following TCR engagement (16). Interestingly, Tex cells require continuous engagement with antigen to persist long term (39), and this occurs in the absence of apoptosis induction, which normally takes place in short-lived Teff cells via AICD.…”

Potential mechanism prediction of Cold-Damp Plague Formula against COVID-19 via network pharmacology analysis and molecular docking

“…Moreover, in the PPI network, the top 10 targets (IL6, TNF, IL10, MAPK8, MAPK3, CXCL8, CASP3, PTGS2, TP53, and MAPK1) were regarded as hub genes that may play important roles in the treatment of COVID-19 by CDPF and are involved in the regulation of immunity and inflammation. For example, TNF has immune regulatory, proinflammatory [70], and anti-viral functions [71], MAPK8 modulates lymphocyte homeostasis [72], IL10 is generally considered to be an anti-inflammatory cytokine [73,74], but production of IL-10 has also been shown to be detrimental during high-dose primary influenza challenge [75]. CXCL8 increases recruitment of principal human neutrophils and is a major inflammatory mediator [76], while PTGS2 is also an inflammatory marker [77].…”